GENETIC-MARKERS FOR GLUTAMIC-ACID DECARBOXYLASE DO NOT PREDICT INSULIN-DEPENDENT DIABETES-MELLITUS IN PAIRS OF AFFECTED SIBLINGS

Reliable genetic and immunological markers are important in the predic tion of insulin-dependent diabetes mellitus (IDDM). Since glutamic aci d decarboxylase (GAD) is a candidate primary autoantigen, we examined the possible linkage between IDDM and the genes encoding GAD(65) (GAD2 , 10p11-12) and GAD(67) (GAD1, 2q31) in 58 Danish IDDM affected sib pa irs. The allelic inheritance of 10 polymorphic dinucleotide repeat seq uences spanning the chromosomal regions of the two GAD genes, were exa mined by affected sib pair analysis (ASP). In addition a restriction f ragment length polymorphism (RFLP) was identified in the gene encoding GAD(65) using the restriction enzyme PvuII. The GAD gene markers were analyzed in relation to the presence of specific HLA types and GAD au toantibodies. No evidence of linkage was found between IDDM and either of the genes encoding GAD. This was also the case when subgroups carr ying specific HLA susceptibility alleles were analyzed. Nor did we obs erve any association between these GAD genetic markers and the presenc e of GAD autoantibodies. Considering the high prevalence of GAD autoan tibodies in IDDM, a putative genetic association between GAD and IDDM would be expected to affect most diabetic individuals. Therefore, our data indicate that the association between GAD and IDDM is not genetic ally determined, and that microsatellites used in this study do not co ntribute to the prediction of IDDM.